The incorporation of polymeric materials in the manufacture of medical devices is well established. Many invasive and non-invasive medical devices incorporating polymeric materials are used daily in the delivery of modern healthcare services. However, the wide use of polymeric materials in medical devices has been associated with an increasing incidence of patient infections. These infections are described in the medical literature as “foreign body induced infections.” These infections are associated with the use of invasive polymeric-containing medical devices to penetrate the physiological skin barrier. This phenomenon is particularly common with indwelling catheters, especially when those catheters are used for extended periods.
Infections are initiated when the polymeric surface of the catheter becomes contaminated with common pathogenic skin bacteria such as Staphylococcus aureus and Staphylococcus epidermidus. The bacteria adhere to the surface of the medical device. The bacterial colonization of the polymer surface is an essential step in the pathogenesis of foreign body infections. Upon adhesion to the surface, the bacteria proliferate and produce a bio-film which is composed of the bacteria's excretion products. The bio-film encourages attachment of the pathogen and provides it with protection from attack by the patient's immune system. As the adhered pathogenic bacteria continue to proliferate, the contamination increases to a level which leads to clinical infection (septic bacterernia). The clinical protocol under this situation calls for removal of the polymeric medical device and treating the patient with both topical and systemic antibiotics.
The incidence of foreign body infections continues to increase in both acute and chronic care settings. Although it is estimated that only 5% of central venous catheters become infected, this equates to approximately 90% of all sepsis cases in intensive care medicine. The infected patients are severely compromised and secondary post treatment costs are high (approximately $25,000-$30,000 per incident).
One strategy to reduce polymeric foreign body infections is to modify the polymer by incorporating antimicrobial materials to inhibit bacterial adhesion and subsequent colonization. This in turn would reduce the chances of bacterial infection. Ideally the antimicrobial additive would be heat stable to facilitate manufacturing processes such as synthesis, extrusion and injection molding. Additionally the antimicrobial additive should be chemically non-reactive to allow for its incorporation into the resin during synthesis to obtain a high level of uniform dispersal. By incorporating the additive during polymer synthesis the requirement for a secondary compounding step is eliminated thus reducing cost and complexity. The antimicrobial additive should also be non-leaching when incorporated into the resin. This will prevent localized cellular destruction when implanted in patients, and will provide a long-lived antibacterial surface and prolonged resistance to bio-film formation and infection.
Antimicrobial agents may be broadly classified into organic and inorganic materials. Organic antimicrobial agents are often complex toxic bactericides which leach from the resin causing health concerns. Organic antimicrobial agents also include antibiotic pharmaceutical preparations which may be added to medical devices. Organic antibiotic agents are often heat labile and readily degraded by heat, humidity and mechanical processing. This makes organic antibiotic agents difficult to incorporate into many resin processing techniques.
Inorganic antimicrobial agents include metal ions, e.g. Ag+, Cu++, Zn++. Silver ions (Ag+) are preferred as they possess wide spectrum antimicrobial activity, safety and heat stability. See generally Guggenbichler et al., 1999 Infection 27 Suppl. 1, S16-S23. The broad spectrum of biocidal activity of silver ions is “oligodynamic” and includes anti-bacterial, anti-fungal and anti-viral activity. Id. The silver ions bind to sulfhydryl groups in enzyme systems and interfere with the transmembrane energy transfer and electron transport in bacterial microorganisms. Id. Silver ions also bind to the DNA of bacterial and fungi thereby increasing the stability of the bacterial double helix and inhibiting proliferation. Id. There is no microbial resistance to silver ions and no cross resistance with antibiotics. Id. The addition of silver ions directly into the resin imparts antimicrobial properties but silver discolors upon exposure to heat, humidity and light.
There are generally two broad methods for incorporating antimicrobial additives to resin systems currently in use. In first method, the antimicrobial agent is added to the finished resin by compounding or kneading the additive into the resin as a secondary processing step. This is often accomplished using melt extrusion and pelletizing equipment and requires the additive to be heat stable for extended periods. The second method involves coating the polymeric product with an agent containing the antimicrobial additive. This method results in an antimicrobial coating which, in many instances, is susceptible to mechanical damage and ultimate loss of the coating and its antimicrobial properties. Each of these methods are performed with prefabricated resin or on fabricated medical devices or device components. The incorporation of the antimicrobial agent is accomplished as one or a series of secondary steps which add cost and complexity to the manufacturing process.
There is therefore a need for a process in which an antimicrobial agent is incorporated during the synthesis of a resin suitable for molding into useful components, and in particular polyurethane for medical devices. This process should produce a resin with a homogeneous distribution of antimicrobial agent without the requirement for a secondary compounding or coating process. Further, there is a need for components that inhibit the development of bio-films. These components may be indwelling medical devices, as well as other medical devices. These components may also be those upon which undesirable biofilms form, such as in food processing, water processing, and marine equipment. The present invention addresses these needs.